Terry, Helen Elizabeth (2010) The development of recombinant Adenoviral vaccines to target pneumovirus infection. PhD thesis, University of Warwick.

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Abstract

Respiratory Syncytial Virus (RSV) is a member of the pneumovirus genus (family
Paramyxoviridae, subfamily Pneumovirinae). RSV is an important respiratory virus
of both infants and the elderly, representing an underappreciated burden on health
care systems. In addition, re-infections can occur despite the presence of pre-existing
immunity, suggesting that immunological memory to RSV is incomplete.
To date, treatment of RSV infection is limited to the provision of supportive care and
no effective vaccine is available. Although several are currently under investigation,
these candidates focus upon the delivery of the F and G antigens of RSV to stimulate
the immune system, rather than the internal antigens, which may provide cross
protection between different subtypes of RSV.
Vaccine development has been greatly hindered by the lack of an appropriate animal
model in which to study vaccine efficacy and pneumovirus pathogenesis. Pneumonia
virus of mice (PVM) is also a member of the Pneumovirus genus and, like RSV
infection of humans, causes a bronchiolitis and fatal pneumonia in its natural host,
the mouse. PVM has been proposed as an appropriate model system in which to both
study pneumovirus pathogenesis and vaccine efficacy.
The PVM model system was adapted to investigate a potential vaccination strategy
to address the lack of an available RSV vaccine. Replication deficient recombinant
adenovirus serotype 5 (rAd5) vectors were constructed which expressed the F, M and
N genes of PVM J3666, in addition to a control construct, which expressed the LacZ
gene of E. coli.
The constructs were administered via the intranasal route to BALB/c mice and were
able to elicit complete protection against a lethal dose of pathogenic PVM J3666, in
both short-term experiments and in a long-term experiment, up to 20 weeks post
immunisation. The protection effect elicited by the constructs was observed when
administered in a single dose, and in alternative mouse strains, C3H/He-mg and
C57BL/6, which had differing immunity haplotypes.
The rAd5 vectors generated a PVM specific IgG humoral response to PVM and Ad5
antigen which did not correlate as the primary mediator of protection. The rAd5
candidate expressing the N gene of PVM was shown to induce IFNγ secreting T-cells.
The use of a peptide library of PVM N protein determined that a specific response
could be identified towards the amino acids N41-90, N81-130, N161-210 and N281-330. Thus,
the PVM infection model of BALB/c mice provides an immunological platform to
facilitate the study of RSV and PVM pathogenesis, immunology and vaccine
development.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QR Microbiology > QR355 Virology
Library of Congress Subject Headings (LCSH):	Respiratory syncytial virus, Paramyxoviruses, Mice -- Vaccination, Adenovirus diseases -- Vaccination
Official Date:	August 2010
Dates:	Date Event August 2010 Submitted
Institution:	University of Warwick
Theses Department:	Department of Biological Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Easton, A. J. (Andrew J.) ; Leppard, Keith
Sponsors:	Medical Research Council (Great Britain) (MRC)
Extent:	xxiv, 301 leaves : ill., charts
Language:	eng

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